A critical component to successful cancer screening is the identification of a lesion for which intervention will result in prolonged survival or cure.The five-year survival of patients with resected stage IA pancreas cancer (the earliest identifiable lesion and <1% of all pancreatic cancer) is approximately 35%. Because of this, current screening paradigms for pancreatic cancer will continue to fail until a curable pancreatic cancer can be identified or until better systemic therapies can be developed. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the only radiographically identifiable precursor lesion of pancreatic cancer and represent an opportunity for intervention prior to the development of pancreatic cancer. Current laboratory, endoscopic, and imaging technologies are unable to distinguish between IPMN that is at low-risk (low-grade dysplasia) or at high-risk (high-grade dysplasia) of becoming malignant. Because of this, clinical decision making is very controversial and markers of high-risk disease are needed. The goal of this multi-institutional research effort is to (specific aim #1) validate a group of protein marker (MMP9, IL-4, sFASL, CA72.4) that we have found to be highly reliable in identifying high- risk IPMN. Recent analyses have identified two separate models of protein markers (sFASL/IL-4 and MMP9/CA72.4) that by themselves had accuracy rates (AUC) of 86% for high-risk disease. We will validate these markers on a multi-institutional set of cyst fluid samples (n=150) utilizing antibody bead array. We will then incorporate these markers (specific aim #2) into a recently developed preoperative prediction model (nomogram) based on clinical and radiographic factors. This model will be developed from a multi- institutional dataset developed by the three participating institutions. This molecular-clinicopathologic nomogram will then be validated (specific aim #3) on a large group of patients enrolled into a prospective multi-institutional tria. The value of identifying markers of high-risk dysplasia in patients with IPMN cannot be overstated. Development of a preoperative test to accurately discriminate between low-risk and high-risk IPMN would allow patients with high-risk lesions to undergo resection prior to the development of an incurable disease, and enable patients with low-risk lesions to avoid operation and spare them the physical, emotional, and financial costs of pancreatectomy.